Effect of rTMS on Anxiety

Examining the Mechanisms of Anxiety Regulation Using a Novel, Sham-controlled, fMRI-guided rTMS Protocol and a Translational Laboratory Model of Anxiety

Given the overall lack of treatment adherence/efficacy, side effects of drugs, and the substantial burden of anxiety disorders on the individual and on the national healthcare system, there is a critical need for mechanistic research into the CNS mechanisms that underlie these disorders. Accordingly, the objective of this grant is to use noninvasive neuromodulation to causally identify the key neural mechanisms that mediate the cognitive symptoms of anxiety. This project is relevant to public health because it has the potential to lead to novel repetitive transcranial magnetic stimulation treatments for pathological anxiety.

Although extensive research has explored the involvement of subcortical structures in arousal, arousal symptoms are only one facet of the symptom profile shared across anxiety disorders. Much less is known about the cognitive symptoms (i.e. difficulty concentrating) experienced by anxiety patients. Accordingly, there is a critical need for mechanistic research into the CNS mechanisms that mediate the cognitive symptoms experienced by anxiety patients. Without such research, treatment development for these disorders will continue to make slow progress. The objective of this application is to determine the key neural mechanisms that mediate the cognitive symptoms of anxiety. The central hypothesis is that the right dorsolateral prefrontal cortex (dlPFC) regulates emotion through top-down inhibition of emotion-related regions. The approach will be to use repetitive transcranial magnetic stimulation (rTMS) to study the effect of right dlPFC activity on objective and subjective measures of induced anxiety, anxiety-related working memory deficits (WM), and TMS-evoked blood oxygenation-level dependent (BOLD) responses during simultaneous TMS/fMRI (i.e. target engagement). The rationale for this approach is that by experimentally manipulating right dlPFC activity using rTMS, this research will be able to causally demonstrate involvement of this region in anxiety regulation, which could translate to future targeted rTMS treatments for anxiety. The first aim will be to determine the effect of a 1-week course of rTMS treatment (1 Hz vs. 10 Hz; right dlPFC target) on anxiety using the threat of unpredictable shock paradigm. The second aim will be to determine the effect of a 1-week course of rTMS treatment (1 Hz vs. 10 Hz; right dlPFC target) on anxiety-related WM-deficits using the Sternberg WM paradigm during threat of shock. The third aim will be to demonstrate target engagement by measuring BOLD responses evoked by TMS pulses to the right dlPFC during threat of shock. The work is innovative because it will combine advanced neuromodulatory techniques (fMRI guidance, electric-field modelling, neuronavigation, active-sham control) with a translational threat of shock paradigm. PUBLIC HEALTH RELEVANCE: Once completed, this research should yield direct evidence for a causal role of the right dlPFC in anxiety regulation, complete with evidence of target engagement, and a novel application to anxiety.

Aims 1 and 2 will be tested using a between-subjects design where 1 group of healthy volunteers will receive 4-day courses of active and sham 1 Hz stimulation to the right dlPFC, while the other group will receive 4-day courses of active and sham 10 Hz stimulation to the right dlPFC. Aim 1, will test the effects of this stimulation on anxiety during the NPU threat task. Aim 2, will test the effects of this stimulation on anxiety-related working memory (WM) deficits using the Sternberg WM paradigm. Aim 3 will be tested using a within-subjects design where this same group of subjects will receive single-pulse active and sham stimulation to the right dlPFC during the Neutral, Predictable, and Unpredictable (NPU) threat task while in the MRI scanner. BOLD activity to the TMS pulses will be the primary outcome measure.

Subjects will receive a continuous train of 1 Hz stimulation until all 3000 pulses are delivered. Consistent with the 10 Hz condition, TMS will occur during the Sternberg WM paradigm.

Subjects will receive 75, 4 second trains at 10 Hz, separated by a 36 second ITI. Stimulation will occur while subjects are doing the Sternberg WM paradigm. The timing of the Sternberg task will be jittered so that each rTMS train will be administered during the maintenance interval of a WM trial.

A Magventure MagPro 100X stimulator with a B65 active/placebo figure-8 coil will be used. The TMS coil will be placed on the head over the target. rTMS intensity will be 100% of the motor threshold (MT), adjusted for field strength difference at motor cortex and target cortex using the individual E-field model. Subjects will receive 3000 pulses/session.

NPU Task: The instructed fear paradigm that will be implemented uses administration of predictable and unpredictable shocks to generate phasic and sustained forms of potentiated startle. The experiment consists of three different conditions: no shock (N), predictable shock (P), and unpredictable shock (U), each lasting approximately 150 sec. In the N condition, no shocks will be delivered. In the P condition, shocks will be administered predictably, that is, only in the presence of a threat cue. In the U condition, the shocks will be unpredictable. In each 150-sec condition, an 8-sec cue will be presented four times. The cue will signal the possibility of receiving a shock only in the P condition. Startle probes will be presented either during the cue period, or the ITI.

NPU Task: The instructed fear paradigm that will be implemented uses administration of predictable and unpredictable shocks to generate phasic and sustained forms of potentiated startle. The experiment consists of three different conditions: no shock (N), predictable shock (P), and unpredictable shock (U), each lasting approximately 150 sec. In the N condition, no shocks will be delivered. In the P condition, shocks will be administered predictably, that is, only in the presence of a threat cue. In the U condition, the shocks will be unpredictable. In each 150-sec condition, an 8-sec cue will be presented four times. The cue will signal the possibility of receiving a shock only in the P condition. Startle probes will be presented either during the cue period, or the ITI.

Sternberg task: On each WM trial, subjects will see a series of 4 letters presented singularly (encoding period) that will be followed by a brief interval where subjects are required to maintain these letters (maintenance period). At the end of the maintenance period, subjects will be prompted to make a response based on the task instructions (response period). The response prompt will consist of a letter and a number. The letter will be chosen from the study series, and the number will correspond to a position in the series. The subjects will indicate whether the position of the letter in the series matches the number.

As with Experiment 1, subjects will have Neutral, Predictable, and Unpredictable periods. During the neutral periods, they will be safe from shocks. During the predictable periods, they can receive shocks but only when there is a cue present. During the unpredictable periods, they will be at risk for shock during the entire duration of the block. Rather than probing their ongoing fear and anxiety with the startle probes, we will replace the startle probes with single TMS pulses to the right dlPFC. This will allow us to causally examine the effect of right dlPFC activity (induced by the TMS pulse) on the neural activity that mediates fear (during the predictable cue) and anxiety (during the unpredictable cue and ITI). Importantly, by replacing the startle probes with TMS pulses, it will be possible to directly compare the TMS-evoked BOLD responses to the pattern of startle responses collected during the MRI/pre-stimulation visit.

Inclusion Criteria: Subjects must be 18-50 years old Able to give their consent Right-handed Exclusion Criteria: Non-english speaking Any significant medical or neurological problems Current or past Axis I psychiatric disorder(s), active or history of active suicidal ideation Alcohol/drug problems in the past year or lifetime alcohol or drug dependence Medications that act on the central nervous system History of seizure History of epilepsy Increased risk of seizure for any reason Pregnancy, or positive pregnancy test IQ <80 Any medical condition that increases risk for fMRI or TMS Any metal in their body which would make having an MRI scan unsafe Any sort of medical implants Hearing loss Claustrophobia